Project Summary Dr. Anand Rohatgi is an Associate Professor in the Department of Internal Medicine/Division of Cardiology at UT Southwestern Medical Center. He has established a successful and independent research program focused on elucidating the role of HDL metabolism in cardiovascular disease. His experiences as an active clinical cardiologist, translational researcher, and mentor have positioned him to be an ideal candidate for the K24 Mentoring Career Development Award. His clinical focus on preventive cardiology and the management of atherosclerotic disease have paved the way for a synergistic translational research program focused on HDL metabolism and atherosclerotic CV disease and a passion for mentoring trainees and faculty. Dr. Rohatgi has applied both epidemiologic and translational POR to this objective, resulting in a number of published observations that have moved the field forward with respect to insights into pathophysiology and refinement of HDL-related markers for risk prediction and as targets of therapy. This work has been supported by continuous funding from the NIH/NHLBI (K08>R01), the AHA, and industry. He has also developed a significant professional interest in mentoring trainees in clinical cardiovascular research and career development. The K24 award will support Dr. Rohatgi?s scientific career activities by allowing him to engage in professional development via coursework/training and execution of novel projects that will enhance the primary aims of his R01 and support future independent funding. In addition to supporting scientific career activities, the K24 award will directly allow Dr. Rohatgi to pursue mentorship/leadership training and enhance his ability to more deeply engage with specific mentees pursuing K and R01 awards and more broadly engage with all mentees in cardiovascular training. The overall scientific aims of this proposal are to: 1) Determine the contribution of genetic factors to variability in cholesterol efflux; 2) Identify circulating metabolites and proteins linked to variation in cholesterol efflux; 3) Determine the miRNA cargo of HDL in those with low versus high cholesterol efflux; 4) Assess the effect of distinct miRNAs identified in #3 on cholesterol efflux transporters and efflux; 5) Among those with extreme elevation in HDL-C, determine the presence of genetic mutations known to correlate with elevated HDL-C (SR-B1, CETP, LIPG) and Lp(a) levels; 6) Determine proteomic and lipidomic signature and functionality of HDL fractions in those with extreme elevations in HDL-C stratified by presence of genetic mutations and elevated Lp(a) levels; 7) Determine the relationship between HDL function measures (cholesterol efflux, HDL particle number, Apo-AI) and high-risk coronary plaque assessed by coronary CT imaging in low risk cohorts.